Tissue adhesives have many potential medical applications, including wound closure, supplementing or replacing sutures or staples in internal surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of viral infection. Additionally, the Fibrin-based adhesives do not covalently bind to the underlying tissue.
Several types of hydrogel tissue adhesives have been developed which have improved adhesive and cohesive properties and are nontoxic. These hydrogels are generally formed by reacting a component having nucleophilic groups with a component having electrophilic groups capable of reacting with the nucleophilic groups of the first component to form a crosslinked network via covalent bonding. However, these hydrogels typically swell or dissolve away too quickly, or lack sufficient adhesion or mechanical strength, thereby decreasing their effectiveness as surgical adhesives.
Kodokian et al. (copending and commonly owned U.S. Patent Application Publication No. 2006/0078536) describe hydrogel tissue adhesives formed by reacting an oxidized polysaccharide with a water-dispersible, multi-arm polyether amine. These adhesives provide improved adhesion and cohesion properties, crosslink readily at body temperature, maintain dimensional stability initially, do not degrade rapidly, and are nontoxic to cells and non-inflammatory to tissue. Hydrogel tissue adhesives with low swell and slow degradation are needed for applications including but not limited to, sealing the dura, ophthalmic procedures, tissue repair, antiadhesive applications, drug delivery, and sealing a fistula or the punctum.
Polysaccharide-based hydrogels are known and various uses have been described, for example, use as a drug carrier (Spiro et al., WO 99/01143), use as a coating on a carrier for use in diagnostic or therapeutic methods (Kirakossian et al., U.S. Pat. No. 7,179,660), and use as a coating for prohibiting post surgical adhesions (Yeo et al., U.S. Patent Application Publication No. 2008/0069857). Additionally, a polysaccharide-based hydrogel formed by reacting oxidized dextran and chitosan for use as a tissue adhesive is described by Goldmann (U.S. Patent Application Publication No. 2005/0002893) and Odermatt et al. (U.S. Patent Application Publication No. 2006/0292030).
Consequently, the problem to be solved is to provide a tissue adhesive material with low swell and a slow degradation rate for use in surgical procedures as well as other medical applications. The stated problem is addressed herein by the discovery that hydrogels formed by the reaction of an aminodextran containing primary amine groups and an oxidized dextran containing aldehyde groups possess these desired properties.